Theresa Guilbert is an Assistant Professor in the Department of Pediatrics and the Arizona Respiratory Center (ARC) at the University of Arizona. Dr. Guilbert is seeking support to focus her efforts on developing, through a combination of coursework and laboratory training, the knowledge and skills needed to pursue investigations into role of human genetic and immune variation as it relates to the development of early childhood respiratory disease. The ARC is a multidisciplinary environment with a long history of successful studies into the epidemiology and etiology of childhood respiratory diseases. Data from recent ARC investigations reveal that children at high risk for respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) who carry a specific polymorphism in the toll-like receptor-4 (TLR4) gene, part of the innate immune system, have different clinical outcomes with RSV infection compared to those who carry other polymorphisms. This difference in outcome may be due to variations in immune responses. We hypothesize that children who carry a specific variant in the TLR4 gene (GG) have decreased amount of airway inflammation compared to children who carry other variations due to decreased production of cytokines, Interleukin-2 (IL-2), IL-4, IL-10, IL-12, IL-13, Interferon-gamma (IFN-gamma,), and a chemokine, Macrophage inflammatory protein 1-alpha (MIP-1alpha). This hypothesis will be addressed by accomplishing the following specific aims: 1) Determine the role of polymorphisms of TLR4 gene the innate immune response to RSV in vivo, and 2) Investigate the role of polymorphisms ofTLR4 gene the innate and adaptive and immune responses in vitro during convalescent phase of RSV infection. Accomplishment of these aims will allow us to begin to elucidate the immune mechanisms of the major gene-environment interactions influencing early childhood respiratory disease.